Bis-basic ketones of dibenzofuran

ABSTRACT

Disclosed herein as novel compounds having antiviral activity are compounds represented by the formula   WHEREIN A is a straight or branched alkylene chain of from 1 to 6 carbon atoms and each Y is the group A.   wherein R1 and R2 are each individually selected from hydrogen, lower alkyl of from 1 to 4 carbon atoms, cycloalkyl of from 3 to 6 carbon atoms, alkenyl of from 3 to 6 carbon atoms and having the vinyl unsaturation in other than the 1-position of the alkenyl group; or B.   wherein X is oxygen or N-R3 and R3 is hydrogen or lower alkyl of from 1 to 4 carbon atoms, OR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS OF SAID COMPOUNDS. The compounds are prepared by several different processes which are described herein.

United States Patent [191 Albrecht et al.

[[4 1 Sept. 16, 1975 BIS-BASIC KETONES OF DIBENZOFURAN [75] Inventors: William L. Albrecht; Robert W.

Fleming, both of Cincinnati, Ohio [73] Assignee: Richardson-Merrell lnc., Wilton,

Conn.

[22] Filed: Sept. 14, 1970 [21] Appl. No.: 72,170

OTHER PUBLICATIONS Whaley et al., J. Org. Chem., l8, 309-312, (1953).

Primary ExaminerDonald G. Daus Assistant Examiner-Jose Tovar Attorney, Agent, or FirmGeorge W. Rauchfuss, Jr.; Eugene O. Retter [57] ABSTRACT Disclosed herein as novel compounds having antiviral activity are compounds represented by the formula wherein A is a straight or branched alkylene chain of from I to 6 carbon atoms and each Y is the group wherein R and R are each individually selected from hydrogen, lower alkyl of from 1 to 4 carbon atoms, cycloalkyl of from 3 to 6 carbon atoms, alkenyl of from 3 to 6 carbon atoms and having the vinyl unsaturation in other than the l-position of the alkenyl group; or

wherein X is oxygen or N]R and R is hydrogen or lower alkyl of from 1 to 4 carbon atoms,

or pharmaceutically acceptable acid addition salts of said compounds.

The compounds are prepared by several different processes which are described herein.

5 Claims, No Drawings BIS-BASIC KETONES OF DIBENZOFURAN benzenoid ring to which such. radical is attached. Thus, one of the groups can be in any of the positions of 1 This invention relates to novel compounds useful an through 4 of the tricyclic ring system, and the other can antiviral agents. More particularly, this invention rebe in any of the positions 6 through 9. Preferably, one lates to bis-basic ketones of dibenzofuran useful as anti- 5 of the basic ketone radicals is in the 2-position and the viral agents. other is in either the 6- or 8-position of the tricyclic ring The novel compounds of this invention include both system. the base form and the Pharmaceutieany acceptable It is apparent from the above Formula I and its deacid addition salts of the base wherein the base is reprei ti h t compounds can h structures h i sented by the formula 10 Y is the group as more fully shown by the following Formula II or 0 wherein Y is the group 5 Formula I N X wherein A is a straight or branched alkylene chain of from 1 to 6 carbon atoms and each Y is the group as more fully shown by the following Formula I.

1 O 0 P R n N-A-C C-AN Formula II RQ/ \RE 0 9 9 X N A-C -AN X L4 Formula III 40 In Formulae II and Ill the various symbols, that is, A, R, R and X have the meanings given hereinbefore.

Each of the symbols A in the compounds of the above Formulae is an alkylene radical having from 1 to wherein R and R are each individually selected 6 Carbon atoms which can be a Straight Chain, that is, from hydrogen, lower alkyl of from 1 to 4 carbon for example, 2-( z)swherein S is a Whole atoms, cycloalkyl f f 3 to 6 carbon atoms, integer of from 0 to 5, or a branched chain. Each of the kenyl of from 3 to 6 carbon atoms and having the alkylene groups as represented y A can be the Same vinyl unsaturation in other than the l position of or different. Preferably these groups are the same. Illusthe alkenyl group; or trative of alkylene groups as represented by A there can be mentioned; for example: methylene, 1,2- ethylene, 1,3-propylene, l,4-butylene, 1,5-pentylene, 1 ,6-hexylene, 2-methyl- 1 ,4-butylene, 2-ethyll ,4-

\X butylene, 3-methyl-1,5,-pentyl.ene and the like. (B) Each amino group of the compounds of Formula II,

that is,

wherein X is oxygen or NR and R is hydrogen or lower alkyl of from 1 to 4 carbon atoms. I 11" Each basic ketone group, that is, the radical can be a primary, a secondary or a tertiary amino fi group. Each R and R is individually hydrogen, lower alkyl having from 1 to about 4 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, alkenyl of from 3 to of Formula I, can be linked to one Of the benzenoid 6 carbon atoms and having the vinyl unsaturation in rings of the tricyclic ring system of dibenzofuran by reother than the l-position of the alkenyl group. Preferaplacement of any of the four hydrogen atoms of the blyeach of the amino groups as represented by is a tertiary amino group.

The term lower alkyl as used in reference to the compounds of Formula II relates to straight or branched alkyl chains having from 1 to 4 carbon atoms. Illustrative of lower alkyls as can be represented by each R or R in the compounds of Formula II there can be mentioned, for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, and the like.

Illustrative of cycloalkyl groups as represented by each of R or R in the compounds of Formula II there can be mentioned, for example: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

When R or R in the compounds of Formula II represents an alkenyl group, the'vinyl unsaturation is in a position other than the l-position of said alkenyl group. Illustrative of alkenyl groups as represented by R and R there can be mentioned, for example: allyl, 3- butenyl, 4-hexenyl and the like.

Each heterocyclic group of Formula III, that is,

in addition to the onenitrogen atom, can contain a second hetero atom,that is, X is oxygen or N-R The R group can be hydrogen or a straight or branched lower alkyl chain of from 1 to about 4 .carbon atoms. As examples of heterocyclic. groups as represented by ethane sulfoniczacid andthelike; :Monoor di-acid salts may be formed, and the salts can be hydrated or substantially anhydrous.

Illustrative of antivirally effective compounds as represented by Formula-Ithere canbe mentioned, for example: 2,8-bis(4-morpholinobutyryl)dibenzofuran, 2,- 8-bis[2-(diethylamino)acetyl]dibenzofuran dihydrochloride v hernihydrate, 2,8-bis-[2-(dime thylamino)acetyl]dibenzofuran dihydrochloride dihydrate, 2,8-bis(4-diallylaminobutyryl)dibenzofuran, 2,8- bis[4-(N-methylcyclohexylamino)butyryl]dibenzofuran, 2,8-bis[4-(N-methylpiperazino)butyryl]dibenzofuran.

One of the methods used to prepare the compounds of this invention is illustrated by the; following reaction:

Formula I In this reaction scheme A and Y have the meanings defined hereinbefoi'e, and each Hal is either chlorine, bromine or ibdine fl'he bis-(w-haloalkanoyl)dibenzofuran derivative, 1, in which the position of substitution is 2,8- or 2,6- can be prepared by Friedel-Crafts acylation of dibenzofuran. Of suitable acylating agents which may be used there can be mentioned, for example: chloroacetyl chloride, bromoacetyl bromide, 3- chloropropionyl chloride, 4-chlorobutyryl chloride, 5- chlorovaleryl chloride, 5- chloro-4-methylvaleryl chloride, 5-chloro-3-methylvaleryl chloride and the like.

It is apparent to those'skilled in the art that the acylation reaction may be carriedout in ;a variety of solvents and under catalysis of a variety of Lewis acids. The temperature and duration of the reaction may bevaried to allow for optimum reaction conditions. A preferred procedure is to combine one equivalent of dibenzofuran with 2.5 equivalents of an acylating agent in methylene chloride followed by portionwise addition of aluminum chloride. The temperature of the reaction is maintained below zero degrees with continuous stirring. After the additions are complete the temperature may be elevated to 2540C. for 12 to 36 hours. The reaction mixture is worked up in the usual manner by decomposing the complex with ice water/I-ICl. The product obtained is recrystallized from methylene chloride, chloroform, or the like. The procedure may be varied such that there is a reverse addition of acylating agent and Lewis acid, or a reverse addition of aromatic hydrocarbon and Lewis acidzThe more reactive halogen derivative, that is, the bis(w-iodoalkanoyl)dibenzofuran may be prepared from the corresponding bischloro derivative using a halogen exchange reaction under the conditions gent rally employed in the Conant-Finkelstein reactionaia Of typical amines, 2, useful in the above reaction, there can be mentioned, for example: ammonia, or a compound which is a potential source of ammonia such as, for example, hexamethylenetetramine and the like;

Alternately, the amination reaction may be carried out on a derivative of compound 1 such as the bis-ketal dibenzofuran derivative, which may be prepared by allowing bis-( w-haloalkanoyl)dibenzofuran and an exprimary amines such as ethylamine, propylamine and 5 cess of ethyl orthoformate to react in the presence of the k and ondary amines such as diethylamine, an acid catalyst such as hydrochloric. acid for several morpholine, Piperaling, y p p and the likedays in a polar solvent such as ethanol, tetrahydrofuran The amination 0f biS-(whaloalkanoyl)dibenzofuran, and the like. The aminoketal derivative is hydrolyzed 1, may be carried out under a variety of conditions. For t th du t of the invention by warming with dilute example, compound .1 may be heated together with a id large excess of the amine, 2, the excess amine serving The compounds of Formula I wherein A is an alkylas the reaction medium and the hydrohalide acceptor. ene h i f 3 to 6 carbon atoms may l b prepared This m thod is particu arly uita le r ea i y ai by the reaction of a Grignard reagent with a dinitrile of able m h excess of which Can be asily removed dibenzofuran as represented by the following reaction:

NC CN XMg(CH Y O 0 H H Y(CH C c-(cH Yefrom the reaction mixture by, for example, distillation In the above reaction X is bromine or chlorine, q is 3 at reduced pressure or by washing the product with wato 6 and Y may be any of the groups defined hereinbe ter. Or, one equivalent of compound I and four equivafore except those which contain a hydrogen attached to lents of the amine, 2, may be heated together in one of the nitrogen atom. a number of different types of solvents, for example, in The rea tion will proceed in from 1 to 24 hours at a aromatic solvents such as benzene, toluene, Xylene, and temperature ranging from room temperature to about the like; or ethers such as tetrahydrofuran, dioxane and 80C. The Grignard reagent, 4, may be prepared by rethe like; or ketoncs such as acetone, butanone and the acting magnesium and an aminoalkyl halide of the forlike; or aprotic solvents such as N,N-dimethylformamula mide, N,N-dimethylacetamide, dimethylsulfoxide and the like; or mixtures of these solvents with water. The reaction between compound 1 wherein the halogen is X(CH2)QY chlorine and the amine, 2, is frequently promoted by the addition of either sodium or potassium iodide, the wherein X, and Y have the meaning defined hereiniodide being used in either catalytic or stoichiomctric above. A preferred solvent for this reaction is tctrahyamounts. In some cases, it may be advantageous to use drofuran. only two equivalents of the amine, 2, for each equiva- The dicyanodibenzofuran derivative, 3, may be prelent of the bis-(w-haloalkanoyl)dibenzofuran, 1, an eX- pared from known diamines by a Sandmeyer reaction cess of an inorganic case such as powdered sodium or on the tetrazonium salts or from known dibenzofuran potassium carbonate being used as the hydrohalide acdicarboxylic acids by dehydration of the corresponding ceptor. The reaction will proceed normally in 12 to 72 hours at temperatures of 20 to 150C. As volatile amines are employed, the reaction is best carried out under pressure in a suitable pressure reactor or auto clavc.

amides by generally known procedures.

The compounds of Formula I wherein A is --CH C- H and each Y is any secondary amine defined hereinbefore may also be prepared by the Mannich reaction represented by the following reaction:

o II II cn c 00H,

II YCHQCHQC By combining one equivalent of compound 6 and two or more equivalents of compound 2 with three or more equivalents of formaldehyde, 7, the reaction will proceed in from 1 to 24 hours in solvents such as water, acetic acid, ethanol, butanol, dioxane, tetrahydrofuran and the like and at temperatures equivalent to the reflux temperature of the solvent. In this reaction two sources of formaldehyde may be employed. When formalin is used the reaction may be conducted with a suspension of compound 6 or a co-solvent such as methanol may be added to allow the reaction to proceed in a homogeneous medium. When the source of formaldehyde is paraformaldehyde the reaction is carried out in an organic solvent such as those mentioned above. It is sometimes desirable to add a slight excess of hydrochloric acid to promote depolymerization of paraformaldehyde either during the reaction or at the end of the reaction.

The secondary amine, compound 2, employed in this reaction may be added to the reaction medium as the hydrochloride salt or as the base form with subsequent in situ formation of the hydrochloride salt by the addition of hydrochloric acid. Of typical secondary amines which may be utilized in the above reaction there can be mentioned, for example: dimethylamine, dibutylamine, morpholine, N-ethylpiperazine and the like.

The diacetyldibenzofuran compound, 6, may be prepared by a Friedel-Crafts acylation reaction on dibenzofuran or by a Grignard reaction of dicyanodibenzofuran, 3, with methylmagnesium halide. The dicyanodibenzofuran compound may be obtained by the methods described hereinbefore.

It has been found that the compounds of this invention are effective for inactivating or inhibiting a broad variety of viruses and can thus be employed as antiviral agents. These compounds are effective for preventing or inhibiting characteristic viral disease symptoms in a host by a wide variety of methods of application and composition. They can be administered for an antiviral effect by means which subject the host, or such host and a virus, to the active ingredients. The host is subjected to the active ingredients by bringing together an active ingredient and host, for example, by applying or contacting the host with such active ingredient or simply administering the active ingredient to the host. This includes subjecting the host to such active ingredient prior to infection with a virus, that is, prophylactic use, as well as subjecting the host to such active ingredient after infection, that is, therapeutic use. Thus, in viable biological material hosts subjected to the active ingredients, the replication of viruses is inhibited when the host is infected before or after being subjected to such ingredients. Also, administration by various routes of the active ingredients to an animal host prior to or after infection with the virus prevents or inhibits viral replication and the development of the various disease conditions characteristic of the particular virus. By the term infection we simply mean invasion of the host with a pathogenic virus. By the term host we 'mean viable biological material or intact animals which are capable of inducing the formation of interferon and which can support the replication of a virus. Preferably the host is of animal and particularly warm-blooded or mammalian origin. Illustrative of hosts for various viruses there can be mentioned: viable biological material such as can be used in the production of vaccines, for example, tissue cultures such as that of kidney, lung, amnion cells, embryos, for example, chick allantoic fluid; and various animals, for example, warmblooded animals such as birds or mammals, including mice, rats, guinea pigs, gerbils, ferrets and the like.

The mode of activity of the active ingredients is not rigorously defined. Inter alia, the active ingredients induce the formation of interferon when a host is subjected to such ingredients. Interferon is a known antiviral substance which is involved with the inhibition of the replication of viruses in the presence of a host cell. Some of the viruses susceptible to replication inhibition by interferon are set forth in l-lorsfall and Tamm, Viral and Rickettsial Infections of Man, 4th Edition 1965), J. B. Lippencott Company, pages 328-329.

The compounds of the present invention can be administered to animals such as warm-blooded animals and particularly mammals to prevent or inhibit infections of: picornavirus, for example, encephalomyocarditis; myxovirus, for example, Influenza A Jap/305); arbovirus, for example, Semliki forest; Herpes virus group, for example, herpes simplex; and poxviruses, for example, Vaccinia IHD. When administered prior to infection, that is, prophylactically, it is preferred that the administration be within 0 to 96 hours prior to infection of the animal with pathogenic virus. When administered therapeutically to inhibit an infection, it is preferred that the administration be within about a day or two after infection with pathogenic virus.

The dosage administered will be dependent upon the virus for which treatment prophylaxis is desired, the

type of animal involved, its age,health, weight, extent of infection, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired. Illustratively, a daily dosage of the active ingredients will generally range from less than about 0.1 to over about 500 mg (milligram) per kg (kilogram) of body weight. Illustratively, dosage levels of the administered active ingredient can be: intravenous, 0.1 to about 10 mg/kg; intraperitoneal 0.1 to about 50 mg/kg; subcutaneous, 0.1 to about 250 mg/kg; oral, 10 to about 250 mg/kg; intranasal instillation 0.1 to about 10 mg/kg; and aerosol b 0.1 to about 10 mg/kg of animal body weight.

The novel compounds, together with conventional pharmaceutical carriers can be employed in unit dosage forms such as solids, for example, tablets or capsules or liquid solutions, suspensions or elixirs for oral administration and injections, or liquid solutions, suspensions, emulsions and the like for parenteral use. The quantity of active ingredients in each dosage will generally differ depending on the type of unit dosage, the type of animal and its weight. Thus, each dosage can contain from less than about 0.1 mg to over 250 mg of active ingredients in a significant quantity of pharmaceutical carrier.

A preferred mode of administration for the compounds (active ingredients) of this invention is parenterally, such as by normally liquid injectable compositions, for example, for intramuscular or subcutaneous administration. In such compositions the quantity of active ingredients can vary from about 0.05 to 20% by weight of the composition and preferably from about 0.1 to 10% by weight. In order to minimize or eliminate irritation at the site of injection, the parenteral compositions can contain a non-ionic surfactant such as those having an HLB (hydrophile-lipophile balance) of about 12 to 17. Such formulations can be solutions, suspensions or emulsions in conventional liquid pharmaceutical carriers, for example, sterile liquids such. as water, saline, and aqueous dextrose (glucose) and related sugar solutions. The quantity of surfactant in the formulation can vary from about 5 to 15% by weight of the formulation. The quantity of a compound of this invention, either in the base form or a pharmaceutically acceptable acid addition salt in such formulations, can vary over a broad range, such as that mentioned hereinbeforc, that is, 0.05 to by weight of the formulation. Preferably, the active ingredient is in the base form. The remaining component or components of such formulations can be a normally liquid pharmaceutical carrier, for example, isotonic aqueous saline, ei ther alone or together with conventional excipients for injectable compositions. The surfactant can be a single surfactant having the above-indicated HLB or a mixture of two or more surfactants wherein such mixture has the indicated HLB. The following surfactants are illustrative of those which can be used in such formulations. (A) Polyoxyethylene derivatives of sorbitan fatty acid esters, such as the TWEEN series of surfactants, for example, TWEEN 80, and the like. The TWEENS are manufactured by Atlas Powder Company. (B) High molecular weight adducts of ethylene oxide with a hydrophobic base formed by the condensation of propylene oxide with propylene glycol, for example, PLU- RONIC F-68 which is manufactured by Wyandotte Chemical Company. The preferred surfactant is Polysorbate 80, U.S.P., apolyoxyethylene sorbitan monooleate.

The following examples are illustrative of the invention.

EXAMPLE 1 2,8-Bis( 4-chlorobutyryl)dibenzofuran To a solution of 30 g (0.18 mole) of dibenzofuran and 62.7 g (0.44 mole) of 4-chlorobutyryl chloride in 1.0 l. of dry methylene chloride previously cooled to 10C. is added portionwise 4-9.9 g (0.37 mole) of aluminum chloride with stirring. When the addition is complete the reaction mixture is heated at reflux for 2 hours, then stirred at room temperature for an additional 12 hours. The reaction mixture is decomposed with ice water/HCl to give the desired product which was recrystallized from isopropyl alcohol. M.P. 102-104C., MHICHCIQ 252, E I790.

EXAMPLE 2 2 8-Bis(5 -chlorovaleryl)dibenzofuran Following the procedure of Example 1, only substituting for 4-chlorobutyryl chloride the appropriate molar equivalent amount of 5-chlorovaleryl chloride, the desired product is obtained.

EXAMPLE 3 4,6-Dicyanodibenzofuran To a mixture of one equivalent of 4,6-dibenzofurandicarboxylic acid [H. Gilman and R. Young, J. Am. Chem. Soc. 57, 1121 (1935)] and 2.2 equivalents of p-toluenesulfonamide is added 4.5 equivalents of phosphorous pentachloride. When the initial reaction subsides, the reaction mixture is heated to 200C. and the solid residue remaining is cooled and treated with pyridine and water. The suspension is filtered, washed with water and suspended in dilute sodium hydroxide solution followed by filtration and washing with water to give 4,6-dicyanodibenzofuran which can be recrystallized from a dimethylformamide-water combination. In

like manner 3,7-dicyanodibenzofuran is prepared from 3,7-dibenzofurandicarboxylic acid [H. Sugii and H. Shindo, J. Phann. Soc. Japan 54, 829 (1934)].

EXAMPLE 4 3 ,8-Dicyanodibenzofuran EXAMPLE 5 Following the procedure of Example 1, only substituting for 4-chlorobutyryl chloride the appropriate molar equivalent amounts of 4-chlorovaleryl chloride, 4-chloro-2-methylbutyryl chloride or 5-chloro-3- methylvaleryl chloride, each of which can be prepared by treating respectively )t-valerolactone, a-methyl-ltbutyrolactone and B-methyLA-valerolactone with thionyl chloride and anhydrous zinc chloride. [0. Wheeler and E. de Rodriguez, J. Org. Chem. 29, 1227 (1964)] the following compounds are prepared: 2,8-bis(4-chlorovaleryl)dibenzofuran, 2,8-bis(4-chloro-2-methylbutyryl)dibenzofuran, and 2,8-bis( 5-chloro-3-methylvaleryl )dibenzofuran.

EXAMPLE 6 2,8-Bis( 4-morpholinobutyryl )dibenzofuran A mixture of 17.0 g (0.045 mole) of 2,8-bis(4- chlorobutyryl)dibenzofuran, 58.4 g (0.8 mole) of morpholine and 2.0 g. of potassium iodide in 500 ml of butanone was heated at reflux for 72 hours then filtered. The filtrate was concentrated to one-half its original volume then diluted with 600 ml of water. The resulting semi-solid was purified by chromatography on neutral alumina using methylene chloride as the eluant. The solvent was removed from the fraction collected leaving a solid residue which was recrystallized from etherpentane to give the desired product. M.P. 9899C., )t 251, E 1470.

EXAMPLE 7 4,6-Bis(4-morpholinobutyryl)dibenzofuran dihydrochloride To a solution of 2.5 equivalents of i 3- morpholinopropyl magnesium chloride, prepared from magnesium and 3-morpholinopropylchloride in tetrahydrofuran, is added dropwise a solution of l equivalent of 4,6-dicyanodibenzofuran dissolved in tetrahydrofuran. After the addition is complete the reaction mixture is gently refluxed for 2 hours then stirred at room temperature for 6 hours. The Grignard complex is decomposed by treating the reaction mixture with saturated ammonium chloride, and the organic mate rial is extracted with chloroform. The chloroform layer is treated with dilute hydrochloric acid with warming, then the aqueous solution is filtered, cooled, made alkaline and extracted with several portions of ether. The ether extracts are combined, dried over magnesium sulfate and treated with ethereal HCl to yield the product which can be purified by crystallization from methanolethyl acetate.

EXAMPLE 8 Following the procedure of Example 7, only substituting for 4,6-dicyanodibenzofuran the appropriate molar equivalent amounts of 3,7-, 3,8- or 2,6- dicyanodibenzofuran respectively, the following compounds are prepared:

3 ,7-bis( 4-morpholinobutyryl )dibenzofuran dihydrochloride,

3 8-bis( 4-morpholinobutyryl )dibenzofuran dihydrochloride, and 2,6-bis(4-morpholinobutyryl)dibenzofuran dihydrochloride.

EXAMPLE 9 2 ,8 'Bis( diethylaminoacetyl )dibenzofuran dihydrochloride hemihydrate To a mixture of 25.0 g (0.078 mole) of 2,8-bis- (chloroacetyl)dibenzofuran and ml of tetrahydrofuran, cooled in an ice/water bath,'was added 100 ml of diethylamine over a 20 minute period. The mixture was refluxed gently for 24 hours then filtered while hot. The solvent was removed in vacuo, and the remaining residue was slurried with ether and filtered. The filtrate was treated with ethereal HCl to give the desired product which was recrystallized from methanolether then from ethanol-ether. M.P. 225227-"C. (dec), h 254, E 1250.

EXAMPLE 10 2,8-Bis(dimethylaminoacetyl)dibenzofuran dihydrochloride dihydrate A mixture of, 24.5 g (0.076 mole) of 2,8-bis(- chloroacetyl)dibenzofuran, 350 ml of tetrahydrofuran and 30.0 g (0.668 mole) of dime thylamine (gas) was heated at 60C. for 24.hours in a Paar pressure bomb. Upon cooling to room temperature the mixture was filtered and the filtrate dried in vacuo. The remaining residue was slurried with ether, filtered, and the filtrate was treated with ethereal HCl to give the desired product which was recrystallized from ethanol-butanone. M.P. 330C., A 254, E 1240.

EXAMPLE 11 EXAMPLE 1 2 Following the procedure of Example 6, only substituting for morpholine the appropriate molar equivalent amounts of N-methylpiperazine, diallylamine. or N-methylcyclohex ylamine, the following compounds are prepared: I

2,8- bis 4-( N methylpiperazino butyryl dibenzofuran,

2,8-bis(4-diallylaminobutyryl)dibenzofuran, and

2,8-bis [4(N-methylcyclohexylamino)butyryl]- dibenzofuran.

What is claimed is:

l. A compound selected from a base of the formula wherein A is a straight or branched alkylcne chain of from 1 to 6 carbon atoms and each Y is the group wherein R and R are each individually selected from hydrogen, lower alkyl of from 1 to 4 carbon atoms, cycloalkyl of from 3 to 6 carbon atoms, alkenyl or from 3 to 6 carbon atoms and having the vinyl unsaturation in other than the 1-position of the alkenyl group; or a pharmaceutically acceptable acid addition salt of said base.

2. A compound of claim 1 wherein one of said groups is in the 2-position of the dibenzofuran ring and the remaining bNrrEn STATES PATENT OFFICE CERMHCATE 0F CCRREC'HCN PATENT NO. 3,906,007 DATED September 16, 1975 INVENTOR(S) William L. Albrecht and Robert W. Fleming;

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 3, "an" should read "as" Column 5, line 58, "case" should read "base" Column 8, line 68, "virus for which treatment prophylaxis" should read "virus for which treatment or prophylaxis". Column 9, line 12, "and aerosol b 0.1" should read "and aerosol 0.1. Column 13, line 7, line 9 of claim 1, "or from" should read "of from".

gigned and fieaicd this first Day 0? June 1976 {semi A nest:

c. MARSHALL DAMN Commissioner oj'Parems and Trademarks RUTH C. MASQN Arresting Officer 

1. A COMPOUND SELECTED FROM A BASE OF THE FORMULA
 2. A compound of claim 1 wherein one of said
 3. A compound of claim 2 where A is a lower alkylene chain having 1 to 4 carbon atoms and each R1 and R2 is lower alkyl of 1 to 4 carbon atoms.
 4. A compound of claim 1 which is 2,8-bis(2(diethylamino)acetyl)dibenzofuran or a pharmaceutically acceptable acid addition salt thereof.
 5. A compound of claim 1 which is 2,8-bis(2-(dimethylamino)acetyl)dibenzofuran or a pharmaceutically acceptable acid addition salt thereof. 